Short synthesis of 3-prenylcoumarins by an unusual prenylation

Article abstract of DOI:10.1080/10916460600946154

Prenylation of coumarins that have hydroxyl or alkoxyl or halo substitution (1a-1i) using 2-methyl-3-butene-2-ol in the presence of boron trifluoride formed 3-prenylcoumarins (2a-2d). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10916460600946154

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Short Synthesis of 3‐Prenylcoumarins by an
Unusual Prenylation
Marellapudi S. Ramachandra a & Gottumukkala V. Subbaraju a
a Laila Research Centre , Jawahar Autonagar, Vijayawada, India
Published online: 01 Dec 2006.
To cite this article: Marellapudi S. Ramachandra & Gottumukkala V. Subbaraju (2006) Short Synthesis of
3‐Prenylcoumarins by an Unusual Prenylation, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:24, 3723-3727, DOI: 10.1080/10916460600946154
To link to this article: http://dx.doi.org/10.1080/10916460600946154
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Synthetic Communicationsw, 36: 3723–3727, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/10916460600946154
Short Synthesis of 3-Prenylcoumarins
by an Unusual Prenylation
Marellapudi S. Ramachandra and
Gottumukkala V. Subbaraju
Laila Research Centre, Jawahar Autonagar, Vijayawada, India
Abstract: Prenylation of coumarins that have hydroxyl or alkoxyl or halo substitution
(1a–1i) using 2-methyl-3-butene-2-ol in the presence of boron trifluoride formed
3-prenylcoumarins (2a–2d).
Keywords: 2-Methyl-3-butene-2-ol, prenylation, 3-prenylcoumarin, synthesis
INTRODUCTION
Coumarins have been known to exhibit a wide range of pharmacological
properties, namely anticoagulant, antimicrobial, antioxidant, cytotoxic
and anti-HIV activities.[1,2] During the synthesis of microfolicoumarin
(6,7-dimethoxy-5-prenylcoumarin),[3] we carried out nuclear prenylation of
6,7-dihydroxycoumarin using 2-methyl-3-butene-2-ol in presence of boron
trifluoride. On methylation followed by chromatography over silica gel, the
crude product yielded an unexpected product in addition to the intended
product, 6,7-dimethoxy-5-prenylcoumarin. The unexpected product was
characterized as 6,7-dimethoxy-3-prenylcoumarin (2a) based on spectral
data.[4] To examine the scope and generality of the formation of 3-prenylcou-
marins, we have investigated the prenylation on other substituted coumarins,
and results are presented here.
Received in India May 8, 2006
Laila Impex communication no. 44.
Address correspondence to Gottumukkala V. Subbaraju, Laila Research Centre,
Unit 1, Phase III, Jawahar Autonagar, Vijayawada 520 007, India. E-mail:
subbarajugottumukkala@hotmail.com
3723

3724
M. S. Ramachandra and G. V. Subbaraju
RESULTS AND DISCUSSION
The widely used methods for direct prenylation of coumarins are 1) reaction of
prenyl bromide and salt of phenoxide moiety and 2) condensation of
coumarins with 2-methyl-3-butene-2-ol in the presence of Et2O–BF3.
Cairns et al.[5] and Mail et al.[6] have reported the synthesis of 3-prenylated
or allylated coumarins by a sequence of [3,3] sigmatropic rearrangements.
To the best of our knowledge, direct prenylation of coumarins to prepare
the 3-prenylcoumarins has not been reported so far.
The prenylation reaction was carried out on the coumarins (1a–i) with
2-methyl-3-butene-2-ol in presence of Et2O–BF3 (Scheme 1), and a series
of 3-prenylcoumarins were isolated. Coumarins 1a–d formed 3-prenylcou-
marins (2a–d) as expected. The products were characterized thoroughly by
spectral data. It appears that a hydroxyl or an alkoxyl group at position C-7
(1a–d) is required to facilitate the formation of 3-prenylcoumarins (2a–d).
Methoxyl at position C-6 (1f) and C-8 (1g) did not lead to the formation of
3-prenylcoumarins. Presence of an alkoxyl or a hydroxyl group at C-6 (1b
and 1c), in addition to oxygen substitution at C-7, allows the formation of
3-prenylcoumarins (2b and 2c). However, coumarins having prenyl or
bromo substitution at C-6 (1h and 1i) prevented the formation of 3-prenyl-
coumarins. Similarly, unsubstituted coumarin (1e) also did not yield the
3-prenylcoumarin.
In conclusion, we have developed a short and straightforward synthesis of
3-prenylcoumarins by direct prenylation using 2-methyl-3-butene-2-ol in the
presence of Et2O–BF3.
EXPERIMENTAL
Melting points were recorded on a Mel-Temp apparatus and are uncorrected.
IR spectra were recorded on a Perkin-Elmer BX1 FT-IR spectrometer.
1H NMR spectra were recorded on AMX 400-MHz NMR spectrometer, and
Scheme 1. a, R ¼ R0 ¼ OMe, R00 ¼ H; b, R ¼ OH, R0 ¼ OMe, R00 ¼ H; c, R ¼ OMe,
R0 ¼ OH, R00 ¼ H; d, R ¼ OH, R0 ¼ R00 ¼ H; e, R ¼ R0 ¼ R00 ¼ H; f, R ¼ R00 ¼ H,
R0 ¼ OMe; g, R ¼ R0 ¼ H, R00 ¼ OMe; h, R ¼ OBn, R0 ¼ Prenyl, R00 ¼ H; and i,
R ¼ OH, R0 ¼ Br, R00 ¼ H.

Synthesis of 3-Prenylcoumarins
3725
13C NMR was recorded on AMX 100-MHz NMR spectrometer; the values for
chemical shifts (d) are given in parts per million (ppm) and coupling constants
(J ) in Hertz (Hz). Mass spectra were recorded on Agilent 1100 series LC/
MSD. All coumarins used in this investigation have been synthesized
according to the literature procedure from the corresponding aldehydes via
the Wittig reaction followed by lactonization.[7]
General Experimental Procedure for the Prenylation of Coumarins
Et2O–BF3 (27.33 mmol), followed by 2-methyl-3-buten-2-ol (45.57 mmol) in
dry dioxan (10 ml), was added to a warm, stirred solution of coumarin
(9.11 mmol) in dry dioxan (50 ml) and then stirred at 858C for 4 h. The
reaction was cooled to rt and poured over aqueous ether (100 ml). The
organic layer was washed with water (30 ml ꢀ 4) and brine solution, dried
over anhydrous Na2SO4, and evaporated. The residue was purified on silica
gel by using hexane–ethyl acetate as an eluent to obtain 3-prenylcoumarins.
6,7-Dihydroxycoumarin (500 mg) was prenylated as described in the
general experimental procedure, and the crude product, without further puri-
fication, was methylated as follows: K2CO3 (637 mg), followed by dimethyl
sulfate (0.18 ml), was added to a stirred solution of the crude prenylated
product (115 mg) in acetone (25 ml). The mixture was refluxed for 4 h. The
inorganic salt was filtered and washed with acetone, and the residue
obtained after evaporation of the solvent from the filtrate was purified on
silica gel using hexane–ethyl acetate (98:2) as an eluent, yielding 2a
(36 mg). On further elution of the column using hexane–ethyl acetate
(95:5), 6,7-dimethoxy-5-prenylcoumarin[3] was obtained as a colorless solid
(30 mg). Compound 2a was identified as 6,7-dimethoxy-3-prenylcoumarin,
and it is identical in all respects with the product obtained by the prenylation
of 6,7-dimethoxycoumarin (1a).
6,7-Dimethoxy-3-prenylcoumarin (2a)
Yield 20%, light yellow solid, mp 88–908C (lit.[4] mp 95–968C); nmax, cm21
:
2962, 1732, 1603, 1557, 1452, 1258, 1059, 819; 1H NMR (methanol-d4): 1.67
(1H, s, H-40), 1.76 (1H, s, H-50), 3.08 (2H, d, J ¼ 7.2 Hz, H-10), 3.84 (3H, s,
H-ArOMe), 3.88 (1H, s, H-ArOMe), 5.24 (1H, t, J ¼ 7.2 Hz, H-20), 6.90
(1H, s, H-8), 7.04 (1H, s, H-5), 7.55 (1H, s, H-4); 13C NMR (methanol-d4):
17.8 (C-40), 25.8 (C-50), 29.7 (C-10), 56.6 (C-Ar-OMe), 56.8 (C-Ar-OMe),
100.8 (C-8), 109.9 (C-5), 113.7 (C-10), 121.0 (C-20), 126.3 (C-3), 136.0
(C-30), 140.4 (C-4), 147.7 (C-6), 149.6 (C-9), 153.8 (C-7), 164.1 (C-2);
liquid chromatograph-mass spectrometer (LCMS) (ESI, positive scan): m/z
297 (M þ Na)þ.
By adopting the general experimental procedure, the following 3-prenyl-
coumarins were also prepared.

3726
M. S. Ramachandra and G. V. Subbaraju
7-Hydroxy-6-methoxy-3-prenylcoumarin (2b)[8]
1
Yield 25%, oil; vmax cm21: 3385, 2930, 1700, 1579, 1286, 772; H NMR
(CDCl3): 1.67 (1H, s, H-40), 1.80 (1H, s, H-50), 3.21 (2H, d, J ¼ 7.2 Hz,
H-10), 3.93 (3H, s, H-ArOMe), 5.30 (1H, t, J ¼ 7.2 Hz, H-20), 6.81 (1H, s,
H-8), 6.89 (1H, s, H-5), 7.35 (1H, s, H-4); LCMS (ESI, positive scan): m/z
283 (M þ Na)þ.
6-Hydroxy-7-methoxy-3-prenylcoumarin (2c)
Yield 12%, colorlessl solid, mp 142–1448C; vmax cm21: 3385, 2930, 1700,
1
1579, 1286, 772; H NMR (CDCl3): 1.68 (1H, s, H-40), 1.80 (1H, s, H-50),
3.22 (2H, d, J ¼ 7.1 Hz, H-10), 3.95 (3H, s, H-ArOMe), 5.29 (1H, t, J ¼ 7.1
Hz, H-20), 6.81 (1H, s, H-8), 6.92 (1H, s, H-5), 7.33 (1H, s, H-4); LCMS
(ESI, positive scan): m/z 283 (M þ Na)þ; analysis calc. for C15H16O4: C,
69.23; H, 6.15. Found: C, 69.05; H, 6.64%.
7-Hydroxy-3-prenylcoumarin (2d)
Yield 10%, colorless solid, mp 118–1208C (lit.[9] mp 122–1238C); vmax
1
cm21: 3298, 2920, 1688, 1610, 1446, 1227, 772; H NMR (CDCl3): 1.69
(1H, s, H-40), 1.80 (1H, s, H-50), 3.22 (2H, d, J ¼ 7.1 Hz, H-10), 5.30 (1H, t,
J ¼ 7.1 Hz, H-20), 6.80 (1H, dd, J ¼ 8.4, 2.0 Hz, H-6), 6.95 (1H, d,
J ¼ 2.0 Hz, H-8), 7.31 (1H, d, J ¼ 8.4 Hz, H-5), 7.41 (1H, s, H-4); LCMS
(ESI, negative scan): m/z 229 (M-H)2.
ACKNOWLEDGMENTS
The authors thank T.-S. Wu and A. G. Damu, National Cheng Kung Univer-
sity, Taiwan, and Sophisticated Instrumentation Facility (SIF), Bangalore, for
NMR spectral data and Sri G. Ganga Raju, chairman, Laila Group, for his
encouragement.
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